'Systems genetics' could revolutionise epilepsy treatment

The ICL team used systems genetics to study a gene network of around 400 genes involved in epilepsy, discovering that an unconnected gene, Sestrin 3 (SESN3), acts as a major regulator of the epileptic gene network.

According to the ICL team, this is the first time SESN3 has been implicated in epilepsy, confirming its coordinating role via studies using both mice and zebrafish.

“Systems genetics allows us to understand how multiple genes work together

Enrico Petretto

Armed with this knowledge, the researchers claimed it may be possible to develop novel anti-epilepsy medications.

Enrico Petretto, from the Medical Research Council (MRC) Clinical Sciences Centre at Imperial College London and co-senior author of the study, said: “Systems genetics allows us to understand how multiple genes work together, which is far more effective than looking at the effect of a gene in isolation. It’s a bit like trying to tackle a rival football team. If you want to stop the team from playing well, you can’t just target an individual player; you first need to understand how the team plays together and their strategy.

“Likewise in systems genetics we don’t look at just one gene at a time, but a network or team of genes and the functional relationships between them in disease.”

Petretto said that with a better understanding of the genetic control point - in this case SESN3 - it may be possible to target epilepsy more effectively.

“This study is proof-of-concept for a new scientific approach in epilepsy

Michael Johnson

“If we can develop medication to target this gene in the brain, then the hope is that we could influence the whole epileptic gene network rather than individual parts and in turn achieve more effective treatments,” Petretto said.

To conduct its study, the ICL team used surgical samples of brain tissue provided by 129 patients who suffer from epilepsy.

“This study is proof-of-concept for a new scientific approach in epilepsy,” said Michael Johnson from Imperial’s Department of Medicine, who co-authored the study.

“Existing epilepsy medications are symptomatic treatments only; that is they act to supress the seizures but they don’t treat the underlying disease,” he said.

NHS statistics suggest that more than 500,000 people in the UK suffer from epilepsy, while more than 50 million are thought to be affected worldwide.

According to Petretto, the ICL team is currently undertaking further research to better understand how SESN3 controls the epileptic gene network and how it could be modified to treat epilepsy.

“We are also planning to broaden the applications of our systems genetics approach to other disorders of the human brain, such as Alzheimer’s disease and neurodevelopmental disorders,” Petretto said.

Meanwhile, Petretto is using systems genetics to study heart and muscle conditions, such as cardiac fibrosis and dilated cardiomiopathy, and intellectual disability and memory conditions.

“Our approach can be applied to any disease where gene regulatory networks can be linked to DNA sequence variation,” Petretto said.